Social, emotional and behavioural aspects of development are key to children’s overall development. A failure to develop normally in any one of these areas can have far reaching consequences, affecting the child’s ability to learn and to develop relationships with peers, potentially leading to fewer educational qualifications, a lack of future employment, poverty and a range of other outcomes including difficulty forming relationships, mental health issues and increased criminal behaviour (Tremblay et al., 2004; Woodward & Fergusson, 2000; Ttofi, Farrington, & Lasel, 2012; Hodgins, Larm, Ellenbogen, Vitaro, C Tremblay, 2013; Pingault et al., 2013). In Glasgow City, a large proportion of children live in disadvantaged circumstances, including living in households and areas suffering from multiple deprivation, living with parental substance misuse and witnessing domestic and community violence (Glasgow Centre for Population Health, 2013; Taulbut & Walsh, 2013). These risk factors can all impact on children’s social, emotional and behavioural development (Margolin & Gordis, 2000a; Gennetian, Castells, & Morris, 2010; Chronis et al., 2003). Children also tend to be clustered in schools with other children who may share similar demographic characteristics and who have similar levels of difficulties, which may compound or ameliorate the individual’s strengths or weaknesses. This thesis aimed to explore the levels of children’s social, emotional and behavioural difficulties at the start of Primary School (age 4-5) and at Primary 3 (age 7-8) in Glasgow city and to investigate the stability of these over time. Analysis was carried out using a brief behavioural screening questionnaire, Goodman’s Strengths and Difficulties Questionnaire (SDQ)(Goodman, 2013b), which had been completed by nursery staff and class teachers. The thesis also aimed to examine whether Glasgow City is different in its levels of social, emotional and behavioural difficulties compared with other areas of Scotland and the UK. Clustering of difficulties within schools is analysed in order to explore the relationships between peer difficulties and demographics, individual difficulties over time and ultimately, whether schools have an effect on the development of social, emotional and behavioural difficulties during the first three years of school. The results of this study indicate that, between preschool and P3, levels of Conduct Problems, Emotional Symptoms and Hyperactivity/inattention increased, whilst levels of abnormal Pro-social Behaviours decreased and Peer Relationship Problems remained relatively static. Both means and prevalence rates for children in Glasgow City demonstrated similar patterns to UK norms, though levels of Hyperactivity/inattention problems at P3 were higher than in UK 5-10 year olds. Data from the Growing Up in Scotland study were used to investigate whether a ‘Glasgow Effect’ (i.e. an amount of variation that could not be explained solely by demographic differences in the population) existed in children’s social, emotional and behavioural difficulties at preschool age. Children in the Glasgow sample did have higher rates of social, emotional and behavioural difficulties compared with children in the rest of Scotland. However, this difference in difficulties appeared be entirely accounted for by the difference in demographics within the populations in the different areas. There are various factors which might explain this: sampling issues, such as having to use a Greater Glasgow and Clyde sample rather than Glasgow City, may mask any Glasgow Effect, whilst it may be that differential attrition in the GUS cohort may mean that children with problems are missing from the sample. It could also be that sleeper effects are at work, which may emerge in the form of difficulties later in childhood, or that what we are seeing is a ‘Scottish Effect’ rather than a Glasgow Effect, given that most of the previous research in this area compared Glasgow with demographically similar English cities. At this stage however, it appears that results from Glasgow may be generalisable to other areas, once demographics are controlled for. Multilevel modelling of Strengths and Difficulties Questionnaire (SDQ) data from Glasgow City schools was then used to explore what factors were associated with longitudinal increases in SDQ scores between preschool and P3. Results showed significant differences between schools in the unadjusted models, accounting for 11% of variance in change scores. The adjusted model found that having worsening social, emotional and behavioural difficulties in the first three years of school was associated with being male, being from a White-UK background, and having had Looked After status (been under the supervision of the state) by preschool. Being in a school with a small school roll was also associated with an increase in difficulties over this time. School effects were only reduced slightly in this final adjusted model, accounting for 9% of variance between schools, suggesting that variation in the development of social, emotional and behavioural difficulties may differ somewhat between schools during the first three years. It should be noted that numbers of pupils within schools were small in some cases, leading to wide confidence intervals and possibly reducing significance of the results. Having social, emotional or behavioural problems at P3 (above the cut-off on the SDQ for likely difficulties) was also related to a range of factors. Again in the unadjusted model, there was a statistically significant difference in levels of difficulties between schools. The strongest predictor of such problems was having had an abnormal score at preschool. Also important was being male, having been Looked After by preschool and being in a school with a higher proportion of children eligible for free school meals, which is likely to be a proxy for income deprivation. However, once these characteristics were controlled for, there was no statistically significant difference between schools. The ability to identify a group of children prior to the start of school who are at risk of continued social, emotional and behaviour difficulties raises questions about whether a preschool mental health screening test should be put in place. It would be hoped that this would allow children to access the support they need in order to optimise their development, with a suggestion that a universal screen for these types of problems could double or treble the traditionally low numbers of children receiving help (Goodman et al., 2000). However, there are also difficulties with a screening tool of this nature, including the potential for false identification of difficulties, the potentially negative impact of labelling children, the additional burden that this may place of services and finally the current lack of evidence around a potential effective intervention for children of this age (Goodman et al., 2000; Sayal et al., 2010; Wichstrom et al., 2012). In conclusion, children in Glasgow City have similar prevalence rates of social, emotional and behavioural difficulties at preschool, compared with children in the rest of the UK, but these difficulties are markedly worse in Glasgow City by the third year of school. However, the difference in these scores may just be due to Glasgow City having a more disadvantaged population, which in turn impacts on levels of difficulties. Whilst schools were found to make a difference in relation to children moving up or down the spectrum of difficulties in the first three years of school, there was no evidence that schools contributed to the likelihood of children having an ‘abnormal’ score at P3, though again, this lack of significance could be related to the small numbers of pupils within some schools, as well as the over-riding impact of having difficulties earlier in life. More research is required with larger numbers of students within schools in order to see if the lack of variance seen between schools at P3 is real or whether it is a sampling issue related to small numbers and therefore wide confidence intervals within schools. Qualitative work around the outliers and some of the unusual findings, e.g. that children in smaller schools appear to fare worse, would be beneficial in interpreting the findings. It would also be of great benefit to follow these children up to the next stage of data collection at P6, in order to explore what happens to children’s social, emotional and behavioural difficulties by the end of Primary school.

Urinary tract infections (UTI) in young children have been associated with serious long-term complications such as renal scarring, hypertension and renal failure. The presenting symptoms of UTI in children are non-specific. If UTI is not suspected, a urine sample is not obtained, and without this, UTI cannot be diagnosed. There is evidence that the diagnosis is often missed. Most published studies have not systematically sampled urine, and those that have are largely based in US emergency departments and only include highly selected groups of children. The true prevalence of UTI in acutely ill children presenting in UK general practice is therefore unknown. My thesis consists of a literature review discussing the association of childhood UTI with long-term complications, the challenges of diagnosis and the evidence that UTIs are being missed; a systematic review of papers reporting UTI prevalence in children which highlights the need for a study in UK general practice; a pilot study to determine the feasibility of recruiting children and obtaining urine samples in UK general practice; and a prospective cohort study to determine the point prevalence of UTI in 597 presenting children, determine the predictive value of presenting symptoms, signs and risk factors, and describe the clinical outcomes for children with UTI. I found that the prevalence of UTI was 5.9% (95% confidence interval: 4.3-8.0%). This may be sufficiently high to justify increased urine sampling in general practice. A multi-variable logistic regression model identified younger age range, pain on passing urine (dysuria) and urinary frequency as being associated with UTI. I propose a urine sampling strategy for GPs assessing acutely ill children and compare this to suspicion-led sampling and current guidelines. In my discussion I discuss the limitations, generalisability and implications of these findings.

Cardiac arrest in paediatric patients often results in death or survival with severe brain injury. Therapeutic hypothermia, lowering of core body temperature to 32 to 34⁰C may reduce injury to the brain in the period after circulation has been restored. This thesis comprises studies related to the feasibility of performing a randomised controlled trial (RCT) of therapeutic hypothermia for neuroprotection after cardiac arrest in the UK. A systematic Cochrane review of paediatric evidence finds no published RCTs supporting or refuting the use of therapeutic hypothermia after cardiac arrest. Four on-going RCTs are identified which will add to the future evidence base; however, a future UK RCT is recommended. Additional support for a RCT is demonstrated by two UK surveys of paediatric intensive care and emergency care clinicians. Current UK practice is varied and clinical equipoise exists regarding post cardiac arrest temperature management. A national, retrospective study of all admissions to paediatric intensive care after out of hospital (OHCA) and in hospital cardiac arrest (IHCA) shows an overall survival of 76 and 50% respectively. Important differences between IHCA and OHCA populations are identified, recommending separation in a RCT. The incidence rate of cardiac arrest admissions to PICU in the UK is too low to recruit to a UK only RCT, after consideration of sample size requirements. A large, multi-centre, retrospective, observational study of OHCA patients identified multiple factors associated with survival. A survival prediction model, incorporating: pupillary reaction, blood lactate level and duration of cardiac arrest, is described. The model could be used as a tool for stratified randomisation within a RCT. Finally, therapeutic hypothermia is retrospectively compared with standard, normothermic temperature management after OHCA. In a limited population, no difference in survival is found; however, important information on application, logistics and safety of the intervention are evaluated.

Cerebral palsy (CP) affects around every one in 500 children born. It isn’t a particular illness or disease, but an umbrella term used to describe a physical condition that affects movement as a result of injury to the brain. There are several types of CP, the main ones being spastic, athetoid and ataxic. Despite medical advances, there is no cure for CP but there are ranges of treatments from drugs to Botulinum toxin type A injections, massage therapy to surgery. The aim of this study is to look at two of these treatments, namely Botulinum toxin type A injections and physiotherapy to treat spastic CP. Botulinum toxin is widely used to reduce muscle tone in the treatment of spasticity in children with cerebral palsy. The aim of the study is to compare the effects treatment with Botulinum toxin type A and Botulinum toxin type A with additional physical therapy in the management of a group of children with cerebral palsy. Experiments were done at The Prince Sultan Hospital and Al-Hada Armed Forces Hospital in Saudi Arabia. The local Ethics Committee approved the protocol. 47 children were recruited. All had cerebral palsy, diplegia, spasticity of the ankle planter flexors and significant gait abnormalities due to dynamic equinus foot deformity. They were divided into two groups. Both groups had their Gross Motor Function assessed one week before injection and at 4 and 6 weeks after injection. Additional measurements of range of movement and stiffness at the ankle and soleus electromyograms were recorded The soleus EMG was silent during ankle dorsiflexion in 20 children four weeks after injection of Botox. The EMG had returned six weeks after injection in every child. The Gross Motor Function Measurements were not significantly different in the two groups before the injection (p=0.23). The measurements improved significantly over the next six weeks in both groups (p<0.001). The magnitude of the improvement was greater in the group, which received Botulinum toxin type A and physical therapy (means 57.2 + 8.90 before, 64.9 + 9.78 after. Mean + SD) than in the group which received Botulinum toxin type A alone (59.5 + 11.0 before, 62.4 + 11.3 after Mean + SD). Conclusions 1. . The Treatment allocation provided groups, which were comparable pre-treatment in terms of baseline GMFM. 2. . Both treatments showed evidence of improvement in GMFM over the period of the study and particularly at 52 weeks. 3. . Treatment 2 showed a significant average advantage in GMFM over Treatment 1 at all times in the study. 4. . This advantage in average GMFM increased from 4 through to 52 weeks with a clear and significant difference between 4 and 52 weeks. 5. . This average advantage appeared to increase the higher the child’s baseline GMFM.

Since the introduction of glucocorticoids (GCs) in the treatment of rheumatoid arthritis in 1949, GC therapy has been associated with a number of adverse effects. Long-term use of GCs can result in growth retardation during childhood due to their actions on growth plate chondrocytes, although the exact mechanisms involved are unclear. The work of this thesis has investigated the cellular and molecular mechanisms involved in mediating GC effects at the growth plate. Affymetrix microarray has been used to identify and characterise the expression of lipocalin 2, a novel GC-responsive chondrocyte gene which may contribute to GC-induced growth retardation in the growth plate. In vitro and in vivo studies have also been used to examine the role of the cell cycle regulator, p21WAF1/CIP1 in GC-induced growth retardation. Finally, the growth plate sparing effects of a novel GC receptor modulator, AL-438, have also been identified. AL438, has reduced effects on bone growth compared to Dex, but maintains similar anti-inflammatory efficacy. This work has not only determined novel mechanisms of GC-induced growth retardation, but has also advanced the search for novel GC receptor modulators with reduced adverse effects.

Brain tissue, both grey and white matter from the cerebral parietal region and the cerebellum, was obtained from 66 infants dying of sudden infant death syndrome. The fatty acid composition was analysed in these tissues by gas liquid chromatography after extraction and derivatisation. The subjects were divided according to their dietary history, either breast or formula feeding. Formula-fed infants were further subdivided according to the content of -linolenic acid in the formula milk. At the time of this study no formula milks analysed contained long chain polyunsaturated fatty acids. Dietary related differences were found in the accretion of polyunsaturated fatty acids into neural membranes. Docosahexaenoic acid concentrations were higher and conversely n-6 series fatty acids lower in breast-fed than formula-fed infants. In cerebral white matter, nervonic acid, the long-chain fatty acid associated with myelination, appeared in breast-fed in advance of formula-fed infants. Similar dietary related differences in polyunsaturated fatty acid compositions were found in the cerebella cortex and the cerebellar white matter was associated with an earlier accretion of nervonic and lignoceric acids when compared to the cerebrum. Analysis of the phospholipid and glycolipid composition of the cerebral and cerebellar white matter tissues was achieved by means of separation by high performance thin layer chromatography followed by scanning densitometry. The results of this study support the need for breast feeding for a minimum of four months. Formulation of manufactured milks should include long chain polyunsaturated fatty acids and nervonic acid at concentrations similar to those of breast milk.

This thesis deals with the quantitative analysis of multiple drugs in the neonate, in blood and in meconium as an alternative biological specimen in forensic toxicology and is also concerned with the dangers of transmission of drugs used and abused by the mother to the foetus and neonate. The aims of the work were to investigate methods for performing a full drug screen on small amounts of biological specimen and to carry out a survey of illicit drug use during pregnancy in the Glasgow area. Following brief overviews of toxicology and the main problems facing the paediatric toxicologist, the development of analytical toxicology procedures to help to overcome them is summarised along with a more detailed examination of solid phase extraction (SPE) - theory, advantages and applications to biological samples. The initial experimental work established the feasibility of performing a full drug screen on small samples of blood such as those obtained from neonates, having a volume of 1-2ml. This used a single SPE cartridge for the extraction of a mixture of acidic and basic drugs followed by end-step analysis with enzyme immunoassay (ELA) and gas chromatography-mass spectrometry (GC/MS). Representative drugs from each group were selected for evaluation purposes: butobarbitone, amylobarbitone, methaqualone, primidone, and phenytoin drugs for the acidic drug group and cocaine, ecgonine methyl ester, morphine, diazepam, and desmethyldiazepam for the basic drug group. These were chosen as examples of drugs commonly used in the UK. Four analytes (morphine, methadone, cocaine and benzoylecgonine) were used to compare two different SPE cartridges, Bond Elut Certify® and Abselut®, which can be used to extract both acidic and basic drugs. The comparison involved four parameters: analyte recovery, lower limits of detection, presence of interferences in the extracts and analysis time required by each. Recoveries were in the range 60-100% and lower limits of detection were in the range 1-25 ng/ml and it was assessed that Bond Elut columns were better than Abselut columns.

This thesis consists of a series of studies utilising quantitative ultrasound (Sunlight Omnisense 7000P) to assess bone health of infants. Preterm infants are at risk of osteopenia of prematurity (OP) which can result in fractures in the short term and may have an impact on growth in infancy and childhood. OP has a multifactorial aetiology including factors such as poor mineral intake and immobility. There is an increasing number of ex-preterm survivors therefore morbidity becomes more important. There is also increasing evidence from epidemiological studies that growth in infancy can have an effect on adult diseases such as osteoporosis. The first study was a cross-sectional study of bone quantitative ultrasound measurements in 110 term and preterm infants shortly after birth. Speed of sound (SOS) was measured at the tibial and the radius. This validated the technique showing reproducible measurements with low inter and intra-observer error, and also showed no benefit to measuring multiple sites. Preterm infants were found to have a significantly lower SOS than term infants. There was a positive correlation between tibial SOS and gestation, with birthweight being a less significant factor than gestation. The second study followed 18 preterm infants longitudinally from birth to hospital discharge or term corrected gestational age (CGA). SOS fell significantly with time in all infants. The most preterm infants had the greatest fall in SOS. SOS at the end of the study period was negatively associated with peak serum alkaline phosphatase and severity of illness score. SOS was significantly lower in the infants who required total parenteral nutrition for longer than 3 weeks. These results show that the neonatal course has a significant impact on SOS trajectory. When preterm infants were followed up in the out-patient clinic over the first two years of life the SOS measurements taken as the next part of this study showed a catch up phenomenon. In the majority of infants, but not all infants, SOS moved into the normal range by 6 months CGA. In the subgroup of infants followed longitudinally those with the lowest SOS at hospital discharge/term corrected age had the greatest increase in SOS over time. An interventional study of passive exercise was performed to explore its role in influencing the bone health of preterm infants. Thirty one infants born at less than 33 weeks gestation were randomised to receive range of motion flexion and extension exercises once daily for 5 days each week starting ‘early’(n=15) or ‘late’ (when on 100kcal/kg/day enteral feeds, n=16) and continuing until term corrected gestational age (CGA) or discharge from hospital. Tibial SOS declined significantly from birth to end of physical activity in both ‘early’ and ‘late’ groups, and this was similar to the decrease seen in a group of historical controls from the earlier longitudinal study. Weight gain and head growth did not show a significant difference between groups or between study infants and controls. No infant was reported to have sustained a fracture, and length of hospital stay was not significantly different between groups. There was no significant increase in sepsis rate, retinopathy of prematurity or chronic lung disease in study infants but numbers were small. On longer term follow-up the intervention was not associated with any adverse effects. To investigate the possibility that the maternal environment plays an important role in influencing infants’ bone health we also studied SOS changes in 188 pregnant women and their offspring. Most women had SOS in the normal range antenatally, and there was no significant change in SOS across pregnancy in the group as a whole. There was a significant negative correlation with SOS SDS and BMI in early pregnancy. Women who smoked cigarettes had lower SOS throughout pregnancy and so did their infants. Serum bone biochemistry was measured in the women antenatally and after delivery, and umbilical cord blood was also taken where possible. Vitamin D deficiency was found to be common at the end of pregnancy. Women of Asian origin had significantly lower vitamin D levels at all stages of pregnancy. There was no significant relationship between maternal and infant SOS, or between maternal vitamin D status and infant SOS. The work of this thesis establishes quantitative ultrasound as a useful technique in the assessment of infant bone health. It is a radiation free tool which provides precise and reproducible measurements in both term and preterm infants. In agreement with a small number of other studies we found that preterm infants have a lower speed of sound at birth compared to term infants; speed of sound increases with increasing gestation while in utero. By including infants who were both appropriately grown and small for gestational age we found maturity to be a more important factor in bone strength than birthweight. Despite the apparent self limiting nature of osteopenia of prematurity an intervention to improve neonatal bone health is still desirable, to prevent fractures. Our results do not substantiate conclusions from previous studies that physical activity alone can improve neonatal bone health. .Findings are however limited by the small sample size. Further studies are needed which investigate alternative exercise regimens, taking into account mineral and nutrient supply. Vitamin D deficiency, smoking and obesity may adversely affect bone health of women and their offspring. In the west of Scotland vitamin D deficiency is common in pregnancy: women of south asian origin are at particularly high risk, and should be supplemented with Vitamin D.

The bacteria located within the human gastrointestinal tract (the gut microbiota) perform numerous protective, immunological and metabolic functions for the host. They are increasingly implicated in the pathogenesis of acquired inflammatory diseases of the gut in childhood, namely: necrotising enterocolitis (NEC) and inflammatory bowel disease (Crohn’s disease (CD) and ulcerative colitis (UC)). Study of the role that the microbiota may play in the development of such diseases may lead to new therapies to modulate or even cure them. However many current techniques depend on the ability to study such bacteria outwith their natural ecosystem. Although molecular techniques can identify species independent of standard cultures they can enlighten little on the metabolic activity of identified bacterial species, which may be important in the propagation of inflammatory responses. Little is known about the potential of novel therapeutic strategies, such as probiotics, to modulate diseases such as NEC. In addition inadequate scientific rigour has been applied to the science of probiotics. The aims of the study described in this dissertation were to test the following hypotheses. Hypotheses: 1. Probiotics prevent NEC in at risk infants of very low birth weight (VLBW). 2. The human gut microbiota can be labelled by stable isotope probing (SIP) to measure metabolic activity. 3. Quantitative measurement of the metabolic activity of the unculturable gut microbiota is a useful way of studying changes in the microbiota, compared with measures of bacterial diversity, and may enlighten our understanding of bacterially mediated inflammatory stimuli in inflammatory gut diseases of childhood.

This study aimed to investigate the effectiveness of Social Stories utilising either photograph or symbol illustrations to address the target behaviours of children with a diagnosis of Autism Spectrum Disorder (ASD). Multiple single-case experiments were conducted utilising an ABA design with 10 participants, all of whom were boys attending mainstream primary schools within a West Midlands Local Authority. The children ranged in age from 5-11 and all of them had a diagnosis and a primary need in relation to ASD. Personalised Social Stories were composed for each of the participants to address a specific target behaviour that had been identified by the child and members of teaching staff. The stories were written by the researcher alongside a member of staff from the Local Authority's Autism Outreach Service and all adhered to the criteria and guidelines for construction outlined by Carol Gray (2004). The format for each of the stories was identical but for the manipulation of the illustrations. The effectiveness of the intervention was monitored using a variety of measures including a Behaviour Log recording the frequency of the target behaviour across each of the experimental phases; the Strengths & Difficulties Questionnaire (Goodman, 1997); and a Teacher / Teaching Assistant Questionnaire that had been designed by the researcher and was based on items contained within the Behaviour Intervention Rating Scale (BIBS) (Elliot & Treuting, 1991). The data obtained from these measures was analysed through the visual inspection of graphical data and the calculation of effect sizes. Discussion is provided about the suitability, reliability and validity of each of the measures and the methods of data analysis. Overall the study provides evidence of the utility and effectiveness of Social Stories for addressing the target behaviours of children with a diagnosis of ASD. Furthermore it offers an original contribution to the existing literature by exploring the impact of different forms of illustration on story efficacy.